Lung cancer is a leading cause of cancer deaths in most industrialized countries (Jemal A, Murray T, Ward E, et al. Cancer statistics, 2005). Despite complete tumor resection in patients with stage I-III non-small-cell lung cancer, distant metastases develop in 50-70 percent of patients.
Adjuvant chemotherapy has been tested to improve survival in patients with completely resected non-small-cell lung cancer. The recently reported International Adjuvant Lung Cancer Trial (IALT) with 1,867 patients, was designed to assess the potential benefit of adjuvant cisplatin-based chemotherapy after complete resection of non-small cell lung cancer. The IALT demonstrated a 4.1 percent absolute benefit in 5-year overall survival in non-small-cell lung cancer patients treated with adjuvant cisplatin-based chemotherapy (the International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 2004). Several other randomized studies have confirmed the benefit of postoperative platinum-based therapy in non-small-cell lung cancer (Gurubhagavatula S, Lynch T J. Semin Respir Crit. Care Med 2005). However, adjuvant chemotherapy only slightly prolongs survival, with a 5-year overall survival improvement ranging from 4 to 15 percent, and gives rise to significant adverse effects (Winton T, et al. N Engl J Med 2005). The identification and quantification of predictive factors for resistance or sensitivity to adjuvant cisplatin-based chemotherapy were therefore needed.
Among potential predictive factors are those involved in cisplatin-resistance such as DNA repair mechanisms. Cisplatin induces cytotoxic effects by binding to DNA and creating platinum-DNA adducts. Some of these adducts establish covalent cross-linking between DNA strands, thereby inhibiting DNA replication. Among the DNA repair pathways, nucleotide excision repair plays a central role and has been associated with resistance to platinum-based chemotherapy (Reed E. Cancer Treat Rev 1998). The excision repair cross-complementation group 1 (ERCC1) enzyme plays a rate-limiting role in the nucleotide excision repair pathway which recognizes and removes cisplatin-induced DNA adducts (Zamble D B. et al. Biochemistry 1996). ERCC1 is also an important factor in DNA interstrand cross-link repair, as well as in recombination processes (De Silva I U. et al. Mol Cell Biol 2000).
For more than a decade, smaller studies have repeatedly reported an association between low ERCC1 mRNA expression levels in several solid tumors and improved clinical outcomes in patients treated with platinum-containing regimens (Dabholkar M. et al J Clin Invest 1994). In particular, Lord et al (Lord R V et al. Clin Cancer Res 2002) reported that ERCC1 mRNA expression predicts response to chemotherapy in advanced non-small-cell lung cancer. Furthermore, by using methodologies such as DNA isolation, enzymatic digestions, and DNA sequencing, two common polymorphisms of the ERCC1 gene (codon 118 C/T and C8092A) were found to be correlated with response to platinum-based chemotherapy in colorectal (Viguier J. et al. Clin Cancer Res 2005) and non-small-cell lung cancer (Zhou W. et al. Clin Cancer Res 2004). These polymorphisms are mainly associated with lower translation rates of the ERCC1 gene, resulting in low expression levels.
The invention described in the international application WO 02/061128 (published on 8 Aug. 2002) relates to prognostic methods for cisplatin-based cancer chemotherapy assessing ERCC1 expression levels. These prognostic tests consist of (i) determining a platinum-based chemotherapy by examination of the amount of ERCC1 mRNA in patient's tumor cells and (ii) comparing it to a pre-determined threshold expression level. Such quantitative gene expression studies were developed for formalin-fixed paraffin-embedded pathological samples because most tumor samples are routinely formalin-fixed paraffin-embedded to allow histological analysis and subsequent archival storage. In this method, all the patients were treated with a platinum-based chemotherapy and the ERCC1 level was assessed so as to prognose the survival probability of the treated patients. Nevertheless, (i) techniques for the isolation and analyses of mRNA from formalin-fixed paraffin-embedded tissue samples are frequently inaccurate, costly and time-consuming and (ii) the conservation of mRNA in formalin-fixed paraffin-embedded samples is eventually affected with time. For these reasons, such analyses are carried out with difficulty by the skilled person, especially in large-scale studies. Other techniques, allowing an easier, more accurate and less expensive measure of the expression of ERCC1 are thus particularly needed.
Moreover, since the study on which the international application WO 02/061128 (published on 8 Aug. 2002) was based did not compare two groups of patients according to whether or not they were treated with cisplatin, the value of ERCC1 mRNA expression as evidenced in this study is only prognostic, and not predictive of the patient response to a chemotherapy.
A biomarker has a “prognostic value” if it enables to distinguish patients with high probability of survival from those who have low probability of survival, regardless of treatment or in a population where all patients received an identical treatment.
On another hand, a biomarker as a “predictive value” for a specific treatment if it enables to distinguish patients who have a high probability of clinical benefit (in terms of survival) from those who will take no benefit from said specific treatment. A predictive value of a biomarker can therefore only be demonstrated when two study groups are compared directly (a treated group against a non-treated group).
Furthermore, other studies have investigated the relation between the expression of different markers, like ERCC1, the platinum resistance and the prognosis in advanced non small cell lung cancer. Indeed, the scientific publication of Huang P Y et al. Chinese Journal of Cancer 2004 aims at determining prognostic values of different markers, like ERCC1, in response of a first-line platinum-based treatment. ERCC1 has been detected by immunohistochemistry. This study indicates that no prognostic value of ERCC1 expression can be demonstrated. On another hand, the publication of Watchers F M et al. Lung Cancer 2005 describes a study to determine a prognostic value of different protein expression involved in DNA repair. Among them, ERCC1 expression is measured in phase III-NSCLC patients by comparing first-line “cisplatin-gemcitabine” and “epirubicin-gemcitabine” chemotherapies. The ERCC1 expression was measured by immunohistochemistry on formalin-fixed, paraffin-embedded tumor biopsies. This document concludes that these markers (including ERCC1) are not prognostic of patient survival after these chemotherapies. Those two documents conclude that ERCC1 has no prognostic value of the efficiency of chemotherapy treatment.